CA2174715A1 - Seco-d steroids active on the cardiovascular system and pharmaceutical compositions containing same - Google Patents
Seco-d steroids active on the cardiovascular system and pharmaceutical compositions containing sameInfo
- Publication number
- CA2174715A1 CA2174715A1 CA002174715A CA2174715A CA2174715A1 CA 2174715 A1 CA2174715 A1 CA 2174715A1 CA 002174715 A CA002174715 A CA 002174715A CA 2174715 A CA2174715 A CA 2174715A CA 2174715 A1 CA2174715 A1 CA 2174715A1
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- beta
- seco
- card
- oxo
- enolide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/42—Singly bound oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Furan Compounds (AREA)
Abstract
Seco-D steroid derivatives having the formula
Description
21 74~ 1 ~
The present invention relates to novel seco-D steroid derivatives active on the cardiovascular system and pharmaceutical compositions containing same for the treatment of cardiovascular disorders such as heart failure and hypertension.
Digitalis products such as digoxin, oubain and digitoxigenin are natural compounds whose activity on the cardiovascular system has long since been known. This activity has been mainly attributed to these compounds ability in inhibiting Na+, K+-ATPase (Repke K.R.H. Schonfeld W. 11984); Na+/K+-ATPase as the digitalis receptor; Trends Pharmacol. Sci. 5: 393-397).
The cis junction between the A/B and the C/D rings of the steroid skeleton is the typical configuration of such derivatives and the one which determines the spatial shape of the digitalis compounds (Thomas R., Gray P., Andrews J. (1990); Digitalis: its mode of action, receptor, and structure-activity relationships; Adv. Drugs Res. 19: 312-562).
Although the compounds claimed herein lack the D-ring of the steroid skeleton and, hence, do not comply with the afore-said structural prerequisite, they surprisingly exhibit good affinity for the Na+, K+-ATPase receptor site and are active on the cardiovascular system.
The compounds of the present invention have the following general formula (I) RI
~V \/
~--R
J~ ~ ,) R
HO
(I) wherein:
R is 3-furyl or 2,5-dihydro-5-oxo-3-furyl;
when R is 3-furyl the symbol ~ represents a single bond;
Rl is methyl or hydroxymethyl;
R2 and R3 are OH and H respectively, or taken together form a keto group;
with the proviso that when R2 and R3 taken together form a keto group, Rl is methyl;
when R is 2,5-dihydro-5-oxo-3-furyl the symbol ----- represents either a single or a double bond;
Rl is methyl, cyano or CH=N ~ R4;
R2 and R3 have the above-specified meaning;
with the proviso that when Rl is CH=N ~ R4, R2 and R3 taken together form a keto group;
with the proviso that when the symbol ~ - represents a double bond, Rl is methyl, and R2, R3 taken together form a keto group;
the symbol ~ represents either the Z or the E isomer;
R4 is NHC(=NH)NR5R6 or oR7;
wherein R5, R6, equal or different, are H or Cl-C4 alkyl; or R5 and R6 taken together can possibly form, with the heteroatom they are linked to, a five- or six-membered monoheterocyclic ring;
R7 is H, CH3 or C2-C6 alkyl, unsubstituted or substituted by NR8R9;
wherein R8 and R9, equal or different, are H or Cl-C4 alkyl.
Should the compounds of formula (I) present themselves as distinct tautomeric forms, it should be understood that the foregoing formula also encompasses such forms. The formula encompasses both Z and E isomers as well as mixtures thereof, the metabolites and the metabolic precursors of the compounds of formula (I).
Also encompassed within the scope of the present invention are the pharmacologically acceptable salts of the compounds of formula (I). By pharmacologically acceptable salts are meant those salts which retain the biological activity of the unsalified parent compound and are derived from such known pharmacologically acceptable acids such as e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, ossalic, malic, tartaric, maleic, citric, methanesulfonic or benzoic acid and others still which will be readily apparent to the average-skilled experts in pharmaceutical technology.
The compounds of the present invention also encompass the solvates such as the hydrates.
Also the N-oxides on the tertiary nitrogen atoms are encompassed in the present invention.
The alkyl groups are straight or branched.
The Cl-C4 alkyl group is preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl.
The NR5R6 group is preferably amino, methylamino, dimethylamino, diethylamino, pyrrolidinyl, piperidyl, 2-dimethylaminoethyl, 2-diethyl-aminoethyl.
Preferred examples of specific compounds according to the present invention are:
1 7B-(3-furyl)- 14, 1 5-seco-5~3-androstan-3~3, 1413-diol 1 7~3- (3-furyl)- 1 4,1 5-seco- 5J3-androstan-313, 1 4B, 1 5-triol 1 7~3-(3-furyl)- 1 4-oxo- 14, 1 5-seco-5J3-androstan-313-ol 313-hydroxy-14-oxo-14,15-seco-5B-card-20122)-enolide 313,14I3-dihydroxy- 14, 15-seco-5B-card-20(22)-enolide 313-hydroxy- 1 4-oxo- 14, 1 5-seco-5~3-card-8, 20(22) -dienolide 21747~5 3B-hydroxy- 14-oxo- 14, 1 5-seco-513-card-20(22)-enolide- 1 5-nitrile 313, 14B-dihydroxy- 14, 1 5-seco-5~3-card-20(22)-enolide- 1 5-nitrile 3-l3-hydroxy-l4-oxo-l4~l5-seco-5B-card-2o(22)enolide-l5-(2-dimeth aminoethoxy- (E)-iminoethyl) 3~3-hydroxy-14-oxo-14,15-seco-5~3-card-20(22)-enolide-15-(2-dimethyl-aminoethoxy- (Z) -iminoethyl) 3~3-hydroxy- 14-oxo- 14,15-seco-513-card-20(22)-enolide- 15-(E)-(guanidino-imino) The invention further provides a process for the preparation of compounds of general formula (I) wherein R is 3-furyl, which comprises reducing the compounds having formula (I) wherein R is 2,5-dihydro-5-oxo-3-furyl, wherein the hydroxy groups are suitably protected e.g. in the form of tetrahydropiranyl ethers, tetrahydrofuranyl ethers, methoxymethyl ethers, ethoxyethyl ethers, silyl ethers such as as e.g. trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl. Other protective groups which are suitable under the chosen reduction conditions may be used.
The reduction reaction is best carried out in inert solvents such as e.g.
diethyl ether, tetrahydrofurane, toluene, methylene chloride, hexane or mixtures thereof in the presence of a complex hydride such as diisobutyl aluminium hydride or 9-borabicyclo [3.3.1]nonane, at a temperature ranging from -78C to the boiling point of the afore-said solvents or their mixtures.
During the work-up of the reaction mixture with diluted aqueous solutions of inorganic acids such as hydrochloric, sulfuric, phosphoric acid or organic acids such as acetic, tartaric, citric, oxalic acid, the protected hydroxy groups are deprotected thus giving the compounds having general formula (I).
The compounds of general formula (I) wherein R has the above-specified meaning and R2 and R3 are OH and H respectively, are obtained from the compounds of formula (I) wherein R2 and R3 taken together form a keto group and wherein the 3-hydroxy group is optionally protected as acetate by reduction with complex hydrides such as e.g. sodium borohydride, tri-t-butoxy lithiumaluminumhydride, sodium cyanoborohydride, in solvents such as e.g. dioxane, methanol, ethanol, tetrahydrofurane or a mixture of such solvents, optionally in the presence of water. To the reaction mixtures, acids such as e.g. hydrochloric acid, hydrobromic, acetic, sulfuric or bases such as e.g. sodium hydroxide or potassium hydroxide can be added to maintain the chosen pH.
The reaction is carried out at a temperature ranging from -78C to room temperature . The reduction of the keto group gives a mixture of ~ epimers in variable proportions depending on the chosen reaction conditions. The B
isomer is isolated from the mixture by crystallisation with suitable solvents such as e . g. ethyl acetate, ethanol, methanol, diethyl ether, hexane, cyclohexane or mixtures thereof, or by silica gel chromatography using e.g.
ethyl acetate, diethyl ether, hexane, cyclohexane or mixture thereof as eluants.
The compounds of general formula (I) wherein R2 and, R3 are OH and H respectively and the 3-hydroxy group is selectively protected by a bulky group such as e.g. t-butyldimethylsilyl group, can be converted to other compounds of general formula (I) wherein R2 and R3 taken together form a keto group, by oxydation via conventional procedures such as e.g. with CrO3.2Py or CrO3 and 2,5-dimethylpyrazole in pyridine or chlorinated solvents;
thionyl chloride, oxalyl chloride or Py.SO3 in DMSO in the presence of triethylamine; morpholine N-oxide and catalitic amounts of tetrapropyl-ammonium perruthenate in the presence of molecular sieves, in chlorinated solvents and/or acetonitrile.
The compounds of general formula lI), wherein R is 2,5-dihydro-5-oxo--3-furyl, Rl is CH=N ~ R4, R2 and R3 taken together form a keto group and R4 has the afore-said meanings, are obtained by condensation reaction of compounds of general formula (II) or (III).
H2NNHC(=NH)NR5R6 H2NoR7 (II) (III) wherein R5, R6 and R7 have the afore-said meanings, with ketoaldehyde (IV) which is a known compound (Cohnen E., Wedemeier K., Sinnwell V. (1982);
Cardenolide, I. D-Ringspaltung von Cardenoliden, Liebigs Ann. Chem. 908-913).
o ~0 ~ ~CHO
AcO
(IV) The compounds (II) and (III) can be used as free bases or as salts with an acid such as, e.g. hydrochloric, hydrobromic, hydriodic, carbonic, oxalic or sulfuric acid.
The reaction can be carried out in a solvent such as ethanol, methanol, acetonitrile, dioxane, tetrahydrofurane optionally in the presence of water or a mixture of the afore-said solvents, at a temperature r~nging from 0C to the boiling point of the above-mentioned solvents or mixtures thereof. Additional salts such as e.g. NaH2PO4, Na2HPO4, NaOAc can be added to the reaction mixture; in order to maintain the chosen pH, acids such as e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, or bases such as e.g. sodium hydroxide or potassium hydroxide can be added.
The 3-hydroxy group is deprotected by acid or basic hydrolysis at the end of the condensation reaction.
The compounds (II) and (III) are commercially available products and g can be prepared by known methods.
All the afore-said conversion reactions are examples of well established organic chemistry procedures (see e.g.: J. March "Advanced Organic Chemistry", J. Wiley & Sons, 1985; D. Barton and W. D. Ollis "Comprehensive Organic Chemistry", Pergamon Press, 1979).
The compounds of general formula (I) prepared according to the present invention as well as their pharmacologically acceptable salts are useful agents for the treatment of cardiovascular disorders such as heart failure and hypertension.
The compounds of general formula (I) prepared according to the present invention as well as their pharmacologically acceptable salts have reduced toxicity compared with positive inotropic agents such as oubain and digitoxin.
The afore-mentioned compounds of general formula (I) show high activity and affinity for the Na+, K+-ATPase receptor site.
To test the affinity for the receptor site of the Na+, K+-ATPase and the agonist or inhibitory activity on the enzyme, the following tests were used:
a) displacement of the specific 3H-oubain binding from the Na+, K+-ATPase receptor purified according to Jorghensen (Jorghensen P., BBA, 1974, 356, 36) and Erdamnn (Erdmann E. et al., Arzneim. Forsh, 1984, 34, 1314);
b) inhibition of the activity of the purified Na+, K~-ATPase measured as % of hydrolysis of 32P-ATP in the presence and in the absence of the tested compound (Doucet A. et al., Am. J. Physiol., 1986, 251, F85 1) .
Systolic blood pressure (SBP) and heart rate (HR) were measured by an indirect tail-cuff plethysmographic method in four-month old pre-hypertensive male rats, (MHS or SHR), i.e. before hypertension onset so as to register the basal value of SBP. The rats were then subdivided in groups of 7 ~nim~ s each and the groups were divided in control and treated group. The compound, suspended in 0.5% (w/v) Methocel, was orally administered daily for at least five weeks. The control group received only Methocel.
SBP and HR were measured weekly, 6 and 24 hours after the treatment.
After five weeks of treatment, when the hypertension was fully developed in the control group (nine months old rats) a one-week wash-out was conducted in order to verify whether SBP would remain low or restored to the basal values of the control group.
The reliability of this method in assessing the hypotensive activity was previously tested on B-blocking agents which did not exhibit any hypotensive activity when administered to hypertensive rats (SHR), but were effective in preventing hypertension development if administered for more than five weeks following weaning (Takeda K. et al., Japan J. Pharmacol., 1979, 29,171;
Takeda K. et al., Japan J. Pharmacol., 1982, 32, 283; Richer C. et al., Eur. J.
Pharmacol., 1978, 47, 393).
The affinity for and the inhibitory activity on the enzyme of some compounds of the present invention are shown in the following table:
Binding 3H-oubain Inhibitory COMPOUND displacement activity -log lCso -log IC50 Comp. I-a 6.2 5.2 Comp. I-b 6.0 5.0 Comp. I-c 5.2 4.3 Comp. I-d 6.7 5.6 Comp. I-e 6.9 5.1 Co m p.I-f 6.1 5.1 Comp. I-g 6.5 5.5 Co m p.I-h 7.0 6.0 Co m p.I-i 5.6 4.0 Co m p.I-l 5.4 4.2 Comp. I-m 5.5 4.1 2t 7~-715 The activity of some compounds in preventing the development of hypertension is shown in the following table:
FFECT OF 5 WEEK TREATMENT IN SPONTANEOUS HYPE~TENSrVE RATS
(MHS) ON THE DEVELOPMENT OF HYPERTENSION.
COMPOUND RATS DOSE * SBP HR
mg/kg/os mm Hg beats/min.
Controls 7 Methocel 172+/-5.0 380+/-6.3 Comp. I-a 7 20 155+/-4.3 370+/-10.5 Comp. I-d 7 20 156+/-4.6 383+/-11.4 Comp. I-h 7 20 160+/-7.8 377+/-10.5 * In 0.5% W/V Methocel The following examples illustrate the invention without limiting it.
E~LAMPLE 1.
17n-(3-furyl~- 14,15-seco-513androstan-3~,141~-diol (I-a~
To a solution of 0.54 g of 3~3,1413-dihydroxy-14,15-seco-513-card-20(22)-enolide (I-e) in THF (13 ml), 1.9 g of imidazole and 1.78 ml of trimethyl-chlorosilane were added. After 1 hour the reaction mixture was poured in water, the suspension thus formed was extracted with EtOAc, the organic phase was separated, washed with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4; the solvent was removed by evaporation under reduced pressure, 716 mg of disilyl ether were obtained as a white foam; the product was used without further purification in the following step.
The present invention relates to novel seco-D steroid derivatives active on the cardiovascular system and pharmaceutical compositions containing same for the treatment of cardiovascular disorders such as heart failure and hypertension.
Digitalis products such as digoxin, oubain and digitoxigenin are natural compounds whose activity on the cardiovascular system has long since been known. This activity has been mainly attributed to these compounds ability in inhibiting Na+, K+-ATPase (Repke K.R.H. Schonfeld W. 11984); Na+/K+-ATPase as the digitalis receptor; Trends Pharmacol. Sci. 5: 393-397).
The cis junction between the A/B and the C/D rings of the steroid skeleton is the typical configuration of such derivatives and the one which determines the spatial shape of the digitalis compounds (Thomas R., Gray P., Andrews J. (1990); Digitalis: its mode of action, receptor, and structure-activity relationships; Adv. Drugs Res. 19: 312-562).
Although the compounds claimed herein lack the D-ring of the steroid skeleton and, hence, do not comply with the afore-said structural prerequisite, they surprisingly exhibit good affinity for the Na+, K+-ATPase receptor site and are active on the cardiovascular system.
The compounds of the present invention have the following general formula (I) RI
~V \/
~--R
J~ ~ ,) R
HO
(I) wherein:
R is 3-furyl or 2,5-dihydro-5-oxo-3-furyl;
when R is 3-furyl the symbol ~ represents a single bond;
Rl is methyl or hydroxymethyl;
R2 and R3 are OH and H respectively, or taken together form a keto group;
with the proviso that when R2 and R3 taken together form a keto group, Rl is methyl;
when R is 2,5-dihydro-5-oxo-3-furyl the symbol ----- represents either a single or a double bond;
Rl is methyl, cyano or CH=N ~ R4;
R2 and R3 have the above-specified meaning;
with the proviso that when Rl is CH=N ~ R4, R2 and R3 taken together form a keto group;
with the proviso that when the symbol ~ - represents a double bond, Rl is methyl, and R2, R3 taken together form a keto group;
the symbol ~ represents either the Z or the E isomer;
R4 is NHC(=NH)NR5R6 or oR7;
wherein R5, R6, equal or different, are H or Cl-C4 alkyl; or R5 and R6 taken together can possibly form, with the heteroatom they are linked to, a five- or six-membered monoheterocyclic ring;
R7 is H, CH3 or C2-C6 alkyl, unsubstituted or substituted by NR8R9;
wherein R8 and R9, equal or different, are H or Cl-C4 alkyl.
Should the compounds of formula (I) present themselves as distinct tautomeric forms, it should be understood that the foregoing formula also encompasses such forms. The formula encompasses both Z and E isomers as well as mixtures thereof, the metabolites and the metabolic precursors of the compounds of formula (I).
Also encompassed within the scope of the present invention are the pharmacologically acceptable salts of the compounds of formula (I). By pharmacologically acceptable salts are meant those salts which retain the biological activity of the unsalified parent compound and are derived from such known pharmacologically acceptable acids such as e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, ossalic, malic, tartaric, maleic, citric, methanesulfonic or benzoic acid and others still which will be readily apparent to the average-skilled experts in pharmaceutical technology.
The compounds of the present invention also encompass the solvates such as the hydrates.
Also the N-oxides on the tertiary nitrogen atoms are encompassed in the present invention.
The alkyl groups are straight or branched.
The Cl-C4 alkyl group is preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl.
The NR5R6 group is preferably amino, methylamino, dimethylamino, diethylamino, pyrrolidinyl, piperidyl, 2-dimethylaminoethyl, 2-diethyl-aminoethyl.
Preferred examples of specific compounds according to the present invention are:
1 7B-(3-furyl)- 14, 1 5-seco-5~3-androstan-3~3, 1413-diol 1 7~3- (3-furyl)- 1 4,1 5-seco- 5J3-androstan-313, 1 4B, 1 5-triol 1 7~3-(3-furyl)- 1 4-oxo- 14, 1 5-seco-5J3-androstan-313-ol 313-hydroxy-14-oxo-14,15-seco-5B-card-20122)-enolide 313,14I3-dihydroxy- 14, 15-seco-5B-card-20(22)-enolide 313-hydroxy- 1 4-oxo- 14, 1 5-seco-5~3-card-8, 20(22) -dienolide 21747~5 3B-hydroxy- 14-oxo- 14, 1 5-seco-513-card-20(22)-enolide- 1 5-nitrile 313, 14B-dihydroxy- 14, 1 5-seco-5~3-card-20(22)-enolide- 1 5-nitrile 3-l3-hydroxy-l4-oxo-l4~l5-seco-5B-card-2o(22)enolide-l5-(2-dimeth aminoethoxy- (E)-iminoethyl) 3~3-hydroxy-14-oxo-14,15-seco-5~3-card-20(22)-enolide-15-(2-dimethyl-aminoethoxy- (Z) -iminoethyl) 3~3-hydroxy- 14-oxo- 14,15-seco-513-card-20(22)-enolide- 15-(E)-(guanidino-imino) The invention further provides a process for the preparation of compounds of general formula (I) wherein R is 3-furyl, which comprises reducing the compounds having formula (I) wherein R is 2,5-dihydro-5-oxo-3-furyl, wherein the hydroxy groups are suitably protected e.g. in the form of tetrahydropiranyl ethers, tetrahydrofuranyl ethers, methoxymethyl ethers, ethoxyethyl ethers, silyl ethers such as as e.g. trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl. Other protective groups which are suitable under the chosen reduction conditions may be used.
The reduction reaction is best carried out in inert solvents such as e.g.
diethyl ether, tetrahydrofurane, toluene, methylene chloride, hexane or mixtures thereof in the presence of a complex hydride such as diisobutyl aluminium hydride or 9-borabicyclo [3.3.1]nonane, at a temperature ranging from -78C to the boiling point of the afore-said solvents or their mixtures.
During the work-up of the reaction mixture with diluted aqueous solutions of inorganic acids such as hydrochloric, sulfuric, phosphoric acid or organic acids such as acetic, tartaric, citric, oxalic acid, the protected hydroxy groups are deprotected thus giving the compounds having general formula (I).
The compounds of general formula (I) wherein R has the above-specified meaning and R2 and R3 are OH and H respectively, are obtained from the compounds of formula (I) wherein R2 and R3 taken together form a keto group and wherein the 3-hydroxy group is optionally protected as acetate by reduction with complex hydrides such as e.g. sodium borohydride, tri-t-butoxy lithiumaluminumhydride, sodium cyanoborohydride, in solvents such as e.g. dioxane, methanol, ethanol, tetrahydrofurane or a mixture of such solvents, optionally in the presence of water. To the reaction mixtures, acids such as e.g. hydrochloric acid, hydrobromic, acetic, sulfuric or bases such as e.g. sodium hydroxide or potassium hydroxide can be added to maintain the chosen pH.
The reaction is carried out at a temperature ranging from -78C to room temperature . The reduction of the keto group gives a mixture of ~ epimers in variable proportions depending on the chosen reaction conditions. The B
isomer is isolated from the mixture by crystallisation with suitable solvents such as e . g. ethyl acetate, ethanol, methanol, diethyl ether, hexane, cyclohexane or mixtures thereof, or by silica gel chromatography using e.g.
ethyl acetate, diethyl ether, hexane, cyclohexane or mixture thereof as eluants.
The compounds of general formula (I) wherein R2 and, R3 are OH and H respectively and the 3-hydroxy group is selectively protected by a bulky group such as e.g. t-butyldimethylsilyl group, can be converted to other compounds of general formula (I) wherein R2 and R3 taken together form a keto group, by oxydation via conventional procedures such as e.g. with CrO3.2Py or CrO3 and 2,5-dimethylpyrazole in pyridine or chlorinated solvents;
thionyl chloride, oxalyl chloride or Py.SO3 in DMSO in the presence of triethylamine; morpholine N-oxide and catalitic amounts of tetrapropyl-ammonium perruthenate in the presence of molecular sieves, in chlorinated solvents and/or acetonitrile.
The compounds of general formula lI), wherein R is 2,5-dihydro-5-oxo--3-furyl, Rl is CH=N ~ R4, R2 and R3 taken together form a keto group and R4 has the afore-said meanings, are obtained by condensation reaction of compounds of general formula (II) or (III).
H2NNHC(=NH)NR5R6 H2NoR7 (II) (III) wherein R5, R6 and R7 have the afore-said meanings, with ketoaldehyde (IV) which is a known compound (Cohnen E., Wedemeier K., Sinnwell V. (1982);
Cardenolide, I. D-Ringspaltung von Cardenoliden, Liebigs Ann. Chem. 908-913).
o ~0 ~ ~CHO
AcO
(IV) The compounds (II) and (III) can be used as free bases or as salts with an acid such as, e.g. hydrochloric, hydrobromic, hydriodic, carbonic, oxalic or sulfuric acid.
The reaction can be carried out in a solvent such as ethanol, methanol, acetonitrile, dioxane, tetrahydrofurane optionally in the presence of water or a mixture of the afore-said solvents, at a temperature r~nging from 0C to the boiling point of the above-mentioned solvents or mixtures thereof. Additional salts such as e.g. NaH2PO4, Na2HPO4, NaOAc can be added to the reaction mixture; in order to maintain the chosen pH, acids such as e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, or bases such as e.g. sodium hydroxide or potassium hydroxide can be added.
The 3-hydroxy group is deprotected by acid or basic hydrolysis at the end of the condensation reaction.
The compounds (II) and (III) are commercially available products and g can be prepared by known methods.
All the afore-said conversion reactions are examples of well established organic chemistry procedures (see e.g.: J. March "Advanced Organic Chemistry", J. Wiley & Sons, 1985; D. Barton and W. D. Ollis "Comprehensive Organic Chemistry", Pergamon Press, 1979).
The compounds of general formula (I) prepared according to the present invention as well as their pharmacologically acceptable salts are useful agents for the treatment of cardiovascular disorders such as heart failure and hypertension.
The compounds of general formula (I) prepared according to the present invention as well as their pharmacologically acceptable salts have reduced toxicity compared with positive inotropic agents such as oubain and digitoxin.
The afore-mentioned compounds of general formula (I) show high activity and affinity for the Na+, K+-ATPase receptor site.
To test the affinity for the receptor site of the Na+, K+-ATPase and the agonist or inhibitory activity on the enzyme, the following tests were used:
a) displacement of the specific 3H-oubain binding from the Na+, K+-ATPase receptor purified according to Jorghensen (Jorghensen P., BBA, 1974, 356, 36) and Erdamnn (Erdmann E. et al., Arzneim. Forsh, 1984, 34, 1314);
b) inhibition of the activity of the purified Na+, K~-ATPase measured as % of hydrolysis of 32P-ATP in the presence and in the absence of the tested compound (Doucet A. et al., Am. J. Physiol., 1986, 251, F85 1) .
Systolic blood pressure (SBP) and heart rate (HR) were measured by an indirect tail-cuff plethysmographic method in four-month old pre-hypertensive male rats, (MHS or SHR), i.e. before hypertension onset so as to register the basal value of SBP. The rats were then subdivided in groups of 7 ~nim~ s each and the groups were divided in control and treated group. The compound, suspended in 0.5% (w/v) Methocel, was orally administered daily for at least five weeks. The control group received only Methocel.
SBP and HR were measured weekly, 6 and 24 hours after the treatment.
After five weeks of treatment, when the hypertension was fully developed in the control group (nine months old rats) a one-week wash-out was conducted in order to verify whether SBP would remain low or restored to the basal values of the control group.
The reliability of this method in assessing the hypotensive activity was previously tested on B-blocking agents which did not exhibit any hypotensive activity when administered to hypertensive rats (SHR), but were effective in preventing hypertension development if administered for more than five weeks following weaning (Takeda K. et al., Japan J. Pharmacol., 1979, 29,171;
Takeda K. et al., Japan J. Pharmacol., 1982, 32, 283; Richer C. et al., Eur. J.
Pharmacol., 1978, 47, 393).
The affinity for and the inhibitory activity on the enzyme of some compounds of the present invention are shown in the following table:
Binding 3H-oubain Inhibitory COMPOUND displacement activity -log lCso -log IC50 Comp. I-a 6.2 5.2 Comp. I-b 6.0 5.0 Comp. I-c 5.2 4.3 Comp. I-d 6.7 5.6 Comp. I-e 6.9 5.1 Co m p.I-f 6.1 5.1 Comp. I-g 6.5 5.5 Co m p.I-h 7.0 6.0 Co m p.I-i 5.6 4.0 Co m p.I-l 5.4 4.2 Comp. I-m 5.5 4.1 2t 7~-715 The activity of some compounds in preventing the development of hypertension is shown in the following table:
FFECT OF 5 WEEK TREATMENT IN SPONTANEOUS HYPE~TENSrVE RATS
(MHS) ON THE DEVELOPMENT OF HYPERTENSION.
COMPOUND RATS DOSE * SBP HR
mg/kg/os mm Hg beats/min.
Controls 7 Methocel 172+/-5.0 380+/-6.3 Comp. I-a 7 20 155+/-4.3 370+/-10.5 Comp. I-d 7 20 156+/-4.6 383+/-11.4 Comp. I-h 7 20 160+/-7.8 377+/-10.5 * In 0.5% W/V Methocel The following examples illustrate the invention without limiting it.
E~LAMPLE 1.
17n-(3-furyl~- 14,15-seco-513androstan-3~,141~-diol (I-a~
To a solution of 0.54 g of 3~3,1413-dihydroxy-14,15-seco-513-card-20(22)-enolide (I-e) in THF (13 ml), 1.9 g of imidazole and 1.78 ml of trimethyl-chlorosilane were added. After 1 hour the reaction mixture was poured in water, the suspension thus formed was extracted with EtOAc, the organic phase was separated, washed with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4; the solvent was removed by evaporation under reduced pressure, 716 mg of disilyl ether were obtained as a white foam; the product was used without further purification in the following step.
2 1 747 1 ~
The disilyl ether was dissolved in anhydrous THF (10 ml) and at the solution, maintained at -50C, 7 ml (lM in hexane) of DIBAL-H were added over 30 min in a nitrogen atmosphere. After one hour, 16 ml of a saturated solution of NaH2PO4 were slowly added while keeping the temperature below -20C; then the reaction mixture was brought to room temperature, the solid obtained was filtered off, washed with EtOAc and eliminated; the aqueous filtrate was extracted with the EtOAc used to wash the solid. The organic phase was separated and washed with a saturated solution of NaHCO3, then with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4. The solvent was then removed by evaporation under reduced pressure. The crude product (intermediate c~, 3-unsaturated lactole) was dissolved in THF (22 ml) and then treated with lN H2SO4 (22 ml) at room temperature for 30 minutes.
The reaction mixture was neutralized by adding solid NaHCO3, the organic solvent was evaporated under reduced pressure and the rem~ining aqueous suspension was extracted with CH2Cl2. The organic phase was separated, washed with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4;
the solvent was removed by evaporation under reduced pressure. The crude product thus obtained was purified by silica gel chromatography, using cyclohexane/EtOAc (70:30 v/v) as eluant; 0.31 g of the compound (I-a) as a white solid were obtained.
lH-NMR(300MHz,CDCl3, ppm from TMS): 0.75(3H,t); 0.93(3H,s);1.00(3H,s);
2.62(1H,dd); 2.81(1H,d); 4.08(1H,bs); 6.30(1H,bs); 7.26(1H,bs); 7.39(1H,bt).
EXA~LE 2 17~3-(3-furyl)-14,15-seco-5n-androstan-3~,14n,15-triol lI-b) The compound (I-b) (0.25 g) was obtained as a white solid starting from 0-45 g of 3B,14~3,15-trihydroxy-14,15-seco-~3-card-20(22)enolide (Cohnen E., Wedemeier K., Sinnwell V. (1982). Cardenolide I. D-Ringspaltung von Cadenoliden. Liebigs Ann. Chem. 908-913), using the procedure described in Ex. 1.
1H-NMR(300MHz,CDCl3,ppm from TMS): 0.96(3H,s); 1.03(3H,s); 2.81(1H,d);
2.94(1H,dd); 3.45(1H,m); 3.55(1H,m); 4.08(1H,bs); 6.37 (lH,bs);
7.00(1H,bs); 7.41(1H,bt).
EXA~LE 3 17~-(3-furyl)-14-oxo-14,15-seco-513-androstan-313-ol (I-c) To a solution of 332 mg of 17B-(3-furyl)-14,15-seco-513-androstan-313,1413-diol (I-a) in DMF (5 ml) maintained at 0C, 634 mg, (9.3 mM) of imidazole and 980 mg of t-butyldimethylcholorosilane were added; the reaction mixture was brought to room temperature and stirred for 19 hours.
The reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was separated, washed with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4; the solvent was removed under reduced pressure to give 384 mg of 3-silyl derivative as a colourless oil, which was used as such in the following step.
The silyl ether was dissolved in 12 ml of CH2Cl2 and 200 mg of powdered 4 A molecular sieves, 285 mg of morpholine N-oxide and 17 mg of tetrapropylammonium perruthenate were added to the solution in sequence.
After 24 hours under vigorous stirring, the reaction mixture was filtered on a layer of silica gel, using cyclohexane/EtOAc (97/3 v/v) as eluant. 0.32 g of 3-silyl ether of (I-c) as colourless oil were obtained.
Such product was deprotected by dissolving it in CHCl3/MeOH (7.5 ml/
15 ml) and adding a drop of concentrated HCl. After 21 hours the reaction mixture was neutralized with a saturated solution of NaHCO3, the organic solvent was evaporated under reduced pressure and the resulting aqueous suspension was extracted with EtOAc; the organic phase was washed with water, dehydrated on anhydrous Na2SO4 and the solvent was removed by evaporation under reduced pressure. The crude product was purified on a silica gel column using cyclohexane/EtOAc (75:25 v/v) as eluant; 0.20 g of the compound (I-c) as a white solid were obtained.
lH-NMR(300MHz,CDCl3,ppm from TMS): 0.81(3H,t); 1.01(3H,s); 1.20(3H,s);
2.62(1H,m); 2.78(1H,dd); 4.09(1H,bs); 6.25(1H,bs); 7.17(1H,bs); 7.34(1H,bt).
EXA~LE 4 313-hydroxy- 14-oxo- 14,15-seco-513-card-20(22)-enolide (I-d~
To a solution of 5 g of 3l3-acetoxy-l4~l5-dioxo-l4~l5-seco-5-l3-card-20(22)-enolide in CH2Cl2 (50 ml) (IV) (Cohnen E., Wedemeier K., Sinnwell V.
(1982). Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Chem.
~ 16 908-913) 1.6 ml of 1,2-ethaneditiol and 1.25 ml of BF3.Et2O were added; an instantaneous reaction took place. After about 10 minutes the reaction mixture was poured in a saturated solution of NaHCO3, the organic phase was separated, washed with water, dehydrated on Na2SO4 and the solvent removed under reduced pressure. The crude product was dissolved in 96% EtOH to which a large excess of nickel Raney was added. The reaction mixture was kept at the reflux temperature for two hours, the solid filtered off and the solvent removed under reduced pressure to give the 3-acetate derivative of (I-d). The crude 3-acetate was dissolved in MeOH and treated with an aqueous solution of 5% HCl at room temperature for 48 hours; the reaction mixture was then neutralized with a saturated solution of NaHCO3, the organic solvent was evaporated under reduced pressure and the resulting aqueous suspension extracted with EtOAc; the organic phase was washed with water, dehydrated on anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified on a silica gel column using hexane/EtOAc (70:30 v/v) as eluant; 3.2 g of the compound (I-d) as a white solid were obtained.
lH-NMR(300MHz,CDCl3,ppm from TMS): 0.89(3H,t); 1.03(3H,s); 1.23(3H,s);
2.57(2H,m); 4.13(1H,bs); 4.70(1H,dd); 4.94(1H,dd) 5.86(1H,bt).
3~,14n-dihydroxy-14,15-seco-5~3-card-20(22)-enolide (I-e) To a solution of 7.0 g of 3B-hydroxy-14-oxo-14,15-seco-5~3-card-20(22)-enolide (I-d) in MeOH (600 ml) kept at -30C, 1.6 g of NaBH4 were added;
after 12 hours the reaction mixture was treated with an aqueous solution of 2~74715 10% HOAc, brought to room temperature and diluted with a saturated solution of NaCl. The organic solvent was evaporated under reduced pressure leaving an aqueous suspension which was extracted with CHCl3. The organic phase was separated, washed with a saturated solution of NaCl, dehydrated on anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified on a silica gel column using EtOAc/ciclohexane (70:30 v/v) as eluant. 1.8 g of the compound (I-e) as a white solid and 3.6 g of 3B,14a-dihydroxy-14,15-seco-5~3-card-20(22)-enolide were obtained.
(I-e) lH-NMR(300MHz,CDC13,ppm from TMS): 0.86(3H,t); 0.94(3H,s);
1.02(3H,s); 2.50(1H,dd); 2.75(1H,m); 4.15(1H,bs); 4.72(1H,dd);
The disilyl ether was dissolved in anhydrous THF (10 ml) and at the solution, maintained at -50C, 7 ml (lM in hexane) of DIBAL-H were added over 30 min in a nitrogen atmosphere. After one hour, 16 ml of a saturated solution of NaH2PO4 were slowly added while keeping the temperature below -20C; then the reaction mixture was brought to room temperature, the solid obtained was filtered off, washed with EtOAc and eliminated; the aqueous filtrate was extracted with the EtOAc used to wash the solid. The organic phase was separated and washed with a saturated solution of NaHCO3, then with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4. The solvent was then removed by evaporation under reduced pressure. The crude product (intermediate c~, 3-unsaturated lactole) was dissolved in THF (22 ml) and then treated with lN H2SO4 (22 ml) at room temperature for 30 minutes.
The reaction mixture was neutralized by adding solid NaHCO3, the organic solvent was evaporated under reduced pressure and the rem~ining aqueous suspension was extracted with CH2Cl2. The organic phase was separated, washed with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4;
the solvent was removed by evaporation under reduced pressure. The crude product thus obtained was purified by silica gel chromatography, using cyclohexane/EtOAc (70:30 v/v) as eluant; 0.31 g of the compound (I-a) as a white solid were obtained.
lH-NMR(300MHz,CDCl3, ppm from TMS): 0.75(3H,t); 0.93(3H,s);1.00(3H,s);
2.62(1H,dd); 2.81(1H,d); 4.08(1H,bs); 6.30(1H,bs); 7.26(1H,bs); 7.39(1H,bt).
EXA~LE 2 17~3-(3-furyl)-14,15-seco-5n-androstan-3~,14n,15-triol lI-b) The compound (I-b) (0.25 g) was obtained as a white solid starting from 0-45 g of 3B,14~3,15-trihydroxy-14,15-seco-~3-card-20(22)enolide (Cohnen E., Wedemeier K., Sinnwell V. (1982). Cardenolide I. D-Ringspaltung von Cadenoliden. Liebigs Ann. Chem. 908-913), using the procedure described in Ex. 1.
1H-NMR(300MHz,CDCl3,ppm from TMS): 0.96(3H,s); 1.03(3H,s); 2.81(1H,d);
2.94(1H,dd); 3.45(1H,m); 3.55(1H,m); 4.08(1H,bs); 6.37 (lH,bs);
7.00(1H,bs); 7.41(1H,bt).
EXA~LE 3 17~-(3-furyl)-14-oxo-14,15-seco-513-androstan-313-ol (I-c) To a solution of 332 mg of 17B-(3-furyl)-14,15-seco-513-androstan-313,1413-diol (I-a) in DMF (5 ml) maintained at 0C, 634 mg, (9.3 mM) of imidazole and 980 mg of t-butyldimethylcholorosilane were added; the reaction mixture was brought to room temperature and stirred for 19 hours.
The reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was separated, washed with a saturated solution of NaCl and dehydrated on anhydrous Na2SO4; the solvent was removed under reduced pressure to give 384 mg of 3-silyl derivative as a colourless oil, which was used as such in the following step.
The silyl ether was dissolved in 12 ml of CH2Cl2 and 200 mg of powdered 4 A molecular sieves, 285 mg of morpholine N-oxide and 17 mg of tetrapropylammonium perruthenate were added to the solution in sequence.
After 24 hours under vigorous stirring, the reaction mixture was filtered on a layer of silica gel, using cyclohexane/EtOAc (97/3 v/v) as eluant. 0.32 g of 3-silyl ether of (I-c) as colourless oil were obtained.
Such product was deprotected by dissolving it in CHCl3/MeOH (7.5 ml/
15 ml) and adding a drop of concentrated HCl. After 21 hours the reaction mixture was neutralized with a saturated solution of NaHCO3, the organic solvent was evaporated under reduced pressure and the resulting aqueous suspension was extracted with EtOAc; the organic phase was washed with water, dehydrated on anhydrous Na2SO4 and the solvent was removed by evaporation under reduced pressure. The crude product was purified on a silica gel column using cyclohexane/EtOAc (75:25 v/v) as eluant; 0.20 g of the compound (I-c) as a white solid were obtained.
lH-NMR(300MHz,CDCl3,ppm from TMS): 0.81(3H,t); 1.01(3H,s); 1.20(3H,s);
2.62(1H,m); 2.78(1H,dd); 4.09(1H,bs); 6.25(1H,bs); 7.17(1H,bs); 7.34(1H,bt).
EXA~LE 4 313-hydroxy- 14-oxo- 14,15-seco-513-card-20(22)-enolide (I-d~
To a solution of 5 g of 3l3-acetoxy-l4~l5-dioxo-l4~l5-seco-5-l3-card-20(22)-enolide in CH2Cl2 (50 ml) (IV) (Cohnen E., Wedemeier K., Sinnwell V.
(1982). Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Chem.
~ 16 908-913) 1.6 ml of 1,2-ethaneditiol and 1.25 ml of BF3.Et2O were added; an instantaneous reaction took place. After about 10 minutes the reaction mixture was poured in a saturated solution of NaHCO3, the organic phase was separated, washed with water, dehydrated on Na2SO4 and the solvent removed under reduced pressure. The crude product was dissolved in 96% EtOH to which a large excess of nickel Raney was added. The reaction mixture was kept at the reflux temperature for two hours, the solid filtered off and the solvent removed under reduced pressure to give the 3-acetate derivative of (I-d). The crude 3-acetate was dissolved in MeOH and treated with an aqueous solution of 5% HCl at room temperature for 48 hours; the reaction mixture was then neutralized with a saturated solution of NaHCO3, the organic solvent was evaporated under reduced pressure and the resulting aqueous suspension extracted with EtOAc; the organic phase was washed with water, dehydrated on anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified on a silica gel column using hexane/EtOAc (70:30 v/v) as eluant; 3.2 g of the compound (I-d) as a white solid were obtained.
lH-NMR(300MHz,CDCl3,ppm from TMS): 0.89(3H,t); 1.03(3H,s); 1.23(3H,s);
2.57(2H,m); 4.13(1H,bs); 4.70(1H,dd); 4.94(1H,dd) 5.86(1H,bt).
3~,14n-dihydroxy-14,15-seco-5~3-card-20(22)-enolide (I-e) To a solution of 7.0 g of 3B-hydroxy-14-oxo-14,15-seco-5~3-card-20(22)-enolide (I-d) in MeOH (600 ml) kept at -30C, 1.6 g of NaBH4 were added;
after 12 hours the reaction mixture was treated with an aqueous solution of 2~74715 10% HOAc, brought to room temperature and diluted with a saturated solution of NaCl. The organic solvent was evaporated under reduced pressure leaving an aqueous suspension which was extracted with CHCl3. The organic phase was separated, washed with a saturated solution of NaCl, dehydrated on anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified on a silica gel column using EtOAc/ciclohexane (70:30 v/v) as eluant. 1.8 g of the compound (I-e) as a white solid and 3.6 g of 3B,14a-dihydroxy-14,15-seco-5~3-card-20(22)-enolide were obtained.
(I-e) lH-NMR(300MHz,CDC13,ppm from TMS): 0.86(3H,t); 0.94(3H,s);
1.02(3H,s); 2.50(1H,dd); 2.75(1H,m); 4.15(1H,bs); 4.72(1H,dd);
4.97(1H,dd); 5.90(1H,bt).
EXA~LE 6 3~3-hydroxy-14-oxo-14,15-seco-513-card-8,20t22)-dienolide (I-fl To a solution of 770 mg of 3~-acetoxy-14-oxo-14,15-seco-513-card-20(22)-enolide (I-d 3-acetate) obtained as described in ex. 4 in THF (23 ml) 0.9 g of pyridinium bromide perbromide were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured in water and extracted with EtOAc; the organic phase was separated and washed with HCl lN and then with a saturated solution of NaCl. The solvent was removed by evaporation under reduced pressure. The oily residue was heated at 70C for 30 minutes and purified by silica gel chromatography using ciclohexane/CH2Cl2/EtOAc (3:2:1 v/v/v) as eluant; obtaining 400 mg of (I-f 3-acetate) which was deprotected by the method described in ex. 4; 200 2~ 7471 5 mg of the compound (I-f) as a white solid were obtained.
lH-NMR(300MHz,CDC13, ppm from TMS): 0.88(3H,t); 1.14(3H,s); 1.17(3H,s);
2.76(1H,dd); 3.92(1H,bs); 4.74(1H,dd); 4.78(1H,dd); 5.83(1H,bt).
EXA~LE 7 3~3-hydroxy-14-oxo-14.15-seco-5n-card-20f22)-enolide-15-nitrile (T~
To a solution of 2.0 g of 3.~3-acetoxy-14-oxo-14,15-seco-5I3-card-20(22)-enolide- 1 5-carboxylic acid (Cohnen E., Wedemeier K., SinnwellV. ( 1982) .
Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Cehm. 908-913) in dioxane (30 ml), 4.0 ml of SOCl2 were added and the reaction mixture was heated at 50C for 2 hours. Afterwards the temperture was raised to 100C and a nitrogen stream was bubbled in the reaction mixture to remove the solvent and the excess of reagent. The residue was dissolved in dioxane (30 ml), and the reaction mixture was cooled to 0C. At this time, gaseous NH3 was bubbled in the solution for 30 minutes; the temperature of the reaction mixture was raised to room temperature, and after one hour 10 ml of CH2Cl2 were added to the mixture. The solid precipitate which formed was filtered off and the solvent evaporated under reduced pressure; 2.5 g of an amide were obtained which was used in the following step without being further purified.
The amide was dissolved in 30 ml of pyridine and 0.82 ml of POCl3 were added to the resulting solution. The reaction mixture was heated at 60C for 24 hours and then poured into a mixture of lN HCl and ice. The suspension thus obtained was extracted with CH2Cl2, the organic phase was separated, washed with water, dehydrated on anhydrous Na2SO4 and the solvent was evaporated under reduced pressure; the residue obtained was treated with diluted acid as described in Ex. 4 and purified by silica gel chromatography using CH2Cl2/EtOAc (50:50 v/v) as eluant; 0.5 g of compound (I-g) as a white solid were obtained.
1H-NMR(300MHz,CDCl3, ppm from TMS): 1.05(3H,s); 1.27(3H,s);
2.59(1H,dt); 2.65(1H,dd); 2.83(1H,dd); 3.10(1H,dd); 4.13(1H,bs);
4.80(1H,dd); 4.88(1H,dd); 6.09(1H,bs).
313,14n-dihydroxy- 14,15-seco-51~-card-20(22)-enolide- 15-nitrile (I-h) To a solution of 1.66 g of 3~3-hydroxy-14-oxo-14,15-seco-5~3-card-20(22)-enolide-15-nitrile lI-g) in MeOH (135 ml) kept at -30C; 240 mg of NaBH4 were added; one hour later, 10 ml of a solution of 10% HOAc were added to the reaction mixture, the temperature was allowed to rise to room temperature and the mixture was diluted with a saturated solution of NaCl.
The organic solvent was evaporated under reduced pressure and the resultant suspension was extracted with CH2Cl2; the organic phase was separated, washed with water, dehydrated on anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography using CH2Cl2/EtOAc (50:50 v/v) as eluant. 0.38 g of the compound (I-h) as a white solid and 0.42 g of 3~3, 14a-dihydroxy-14,15-seco-5B-card-20(22)-enolide- 15-nitrile were obtained.
(I-h) lH-NMR(300MHz,CDCl3/CD3OD, ppm from TMS): 0.89 (3H,s);
0.99(3H,s); 2.49(1H,dd); 2.72(1H,d); 2.81(1H,dd); 3.05(1H,dd);
4.07(1H,bs); 4.80(1H,dd); 4.98(1H,dd); 6.02(1H,bs).
EXA~LE 9 3~3-hydroxy-14-oxo-14,15-seco-5n-card-20(22)-enolide-15-(2-dimethyl-aminoetho2~y-(E)-iminoethyl) (I-i) and 3J3-hydroxy-14-oxo-14,15-seco-S13-card-20(22)-enolide- 15(2-dimethylaminoethoxy-(Z)-iminoethyl (I-l) A solution of 0.5 g of 3~ acetoxy-14,15-dioxo-14,15-seco-5B-card-20(22)-enolide (IV) (Cohnen E., Wedemeier K., Sinnwell V. (1982).
Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Chem. 908-913), 0.2 g of sodium acetate and 0.42 g of 2-dimethylaminoethoxyamine dichlorohydrate, in 70 ml of 96% ethanol was heated at 50C for two hours.
The organic solvent was removed by evaporation under reduced pressure and the residue was extracted with CH2Cl2 and water. The organic phase was separated, washed with water, dehydrated on anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude residue was dissolved in methanol (100 ml) and hydrolyzed in an acid environment as described in Ex. 4. After purification on a silica gel column using CH2Cl2/MeOH (90/10 v/v) as eluant; 0.15 g of the compound (I-i) as a white foam and 0.18 g of compound (I-l) as a yellowish foam were obtained.
(I-i) 1H-NMR(300MHz,CDCl3,ppm from TMS):1.05(3H,s); 1.28(3H,s);
2.27(3H,s); 2.35-3.10(6H,m); 4.08(2H,t); 4.14(1H,m);
4.25-4.95(2H,m); 5.91(1H,m); 7.36(1H,dd).
(I-l) 1H-NMR(300MHz,CDCl3,ppm from TMS):1.05(3H,s); 1.28(3H,s);
2.31(3H,s); 2.35-3.07(6H,m); 4.14(1H,m); 4.16(2H,t);
4.68-4.90(2H,m); 5.91 (lH~m); 6.57( lH,dd).
313-hydroxy-14-oxo-14.15-seco-513-card-20(22~ enolide-15-tE) -(~uanidin~
imino) (I-m) To a solution of 0.5 g of 3l3-acethoxy-14,15-dioxo-14,15-seco-5-l3-card-20(22)-enolide (IV) (Cohnen E., Wedemeier K., Sinnwell V. (1982).
Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Chem. 908-913) in 25 ml of a mixture (1: 1 v/v) of dioxane and water, 0.19 g of aminoguanidine bicarbonate dissolved in 10 ml of the same solvent mixture were added. The reaction mixture was heated at the reflux temperature for one hour and the organic solvent was removed by evaporation under reduced pressure. The aqueous suspension thus obtained was extracted with a (9:1 v/v) mixture of CHCl3/MeOH; the organic phase was separated, washed with a saturated solution of NaCl, dehydrated on anhydrous Na2SO4 and the solvent was removed by evaporation under reduced pressure. The residue thus obtained was treated with diluted acid as described in Ex, 4 and purified by silica gel chromatography using CHCl3/MeOH/NH4OH (80/20/2 v/v/v) as eluant. 0.15 g of the title compound were obtained as a white solid.
lH-NM~(300MHz,DMSO-D6,ppm from TMS): 0.99(3H,s); 1.19(3H,s);
2.01(3H,s); 2.30-2.70(3H,m); 3.18(1H,dd); 4.81(2H,m); 4.91(1H,m);
EXA~LE 6 3~3-hydroxy-14-oxo-14,15-seco-513-card-8,20t22)-dienolide (I-fl To a solution of 770 mg of 3~-acetoxy-14-oxo-14,15-seco-513-card-20(22)-enolide (I-d 3-acetate) obtained as described in ex. 4 in THF (23 ml) 0.9 g of pyridinium bromide perbromide were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured in water and extracted with EtOAc; the organic phase was separated and washed with HCl lN and then with a saturated solution of NaCl. The solvent was removed by evaporation under reduced pressure. The oily residue was heated at 70C for 30 minutes and purified by silica gel chromatography using ciclohexane/CH2Cl2/EtOAc (3:2:1 v/v/v) as eluant; obtaining 400 mg of (I-f 3-acetate) which was deprotected by the method described in ex. 4; 200 2~ 7471 5 mg of the compound (I-f) as a white solid were obtained.
lH-NMR(300MHz,CDC13, ppm from TMS): 0.88(3H,t); 1.14(3H,s); 1.17(3H,s);
2.76(1H,dd); 3.92(1H,bs); 4.74(1H,dd); 4.78(1H,dd); 5.83(1H,bt).
EXA~LE 7 3~3-hydroxy-14-oxo-14.15-seco-5n-card-20f22)-enolide-15-nitrile (T~
To a solution of 2.0 g of 3.~3-acetoxy-14-oxo-14,15-seco-5I3-card-20(22)-enolide- 1 5-carboxylic acid (Cohnen E., Wedemeier K., SinnwellV. ( 1982) .
Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Cehm. 908-913) in dioxane (30 ml), 4.0 ml of SOCl2 were added and the reaction mixture was heated at 50C for 2 hours. Afterwards the temperture was raised to 100C and a nitrogen stream was bubbled in the reaction mixture to remove the solvent and the excess of reagent. The residue was dissolved in dioxane (30 ml), and the reaction mixture was cooled to 0C. At this time, gaseous NH3 was bubbled in the solution for 30 minutes; the temperature of the reaction mixture was raised to room temperature, and after one hour 10 ml of CH2Cl2 were added to the mixture. The solid precipitate which formed was filtered off and the solvent evaporated under reduced pressure; 2.5 g of an amide were obtained which was used in the following step without being further purified.
The amide was dissolved in 30 ml of pyridine and 0.82 ml of POCl3 were added to the resulting solution. The reaction mixture was heated at 60C for 24 hours and then poured into a mixture of lN HCl and ice. The suspension thus obtained was extracted with CH2Cl2, the organic phase was separated, washed with water, dehydrated on anhydrous Na2SO4 and the solvent was evaporated under reduced pressure; the residue obtained was treated with diluted acid as described in Ex. 4 and purified by silica gel chromatography using CH2Cl2/EtOAc (50:50 v/v) as eluant; 0.5 g of compound (I-g) as a white solid were obtained.
1H-NMR(300MHz,CDCl3, ppm from TMS): 1.05(3H,s); 1.27(3H,s);
2.59(1H,dt); 2.65(1H,dd); 2.83(1H,dd); 3.10(1H,dd); 4.13(1H,bs);
4.80(1H,dd); 4.88(1H,dd); 6.09(1H,bs).
313,14n-dihydroxy- 14,15-seco-51~-card-20(22)-enolide- 15-nitrile (I-h) To a solution of 1.66 g of 3~3-hydroxy-14-oxo-14,15-seco-5~3-card-20(22)-enolide-15-nitrile lI-g) in MeOH (135 ml) kept at -30C; 240 mg of NaBH4 were added; one hour later, 10 ml of a solution of 10% HOAc were added to the reaction mixture, the temperature was allowed to rise to room temperature and the mixture was diluted with a saturated solution of NaCl.
The organic solvent was evaporated under reduced pressure and the resultant suspension was extracted with CH2Cl2; the organic phase was separated, washed with water, dehydrated on anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography using CH2Cl2/EtOAc (50:50 v/v) as eluant. 0.38 g of the compound (I-h) as a white solid and 0.42 g of 3~3, 14a-dihydroxy-14,15-seco-5B-card-20(22)-enolide- 15-nitrile were obtained.
(I-h) lH-NMR(300MHz,CDCl3/CD3OD, ppm from TMS): 0.89 (3H,s);
0.99(3H,s); 2.49(1H,dd); 2.72(1H,d); 2.81(1H,dd); 3.05(1H,dd);
4.07(1H,bs); 4.80(1H,dd); 4.98(1H,dd); 6.02(1H,bs).
EXA~LE 9 3~3-hydroxy-14-oxo-14,15-seco-5n-card-20(22)-enolide-15-(2-dimethyl-aminoetho2~y-(E)-iminoethyl) (I-i) and 3J3-hydroxy-14-oxo-14,15-seco-S13-card-20(22)-enolide- 15(2-dimethylaminoethoxy-(Z)-iminoethyl (I-l) A solution of 0.5 g of 3~ acetoxy-14,15-dioxo-14,15-seco-5B-card-20(22)-enolide (IV) (Cohnen E., Wedemeier K., Sinnwell V. (1982).
Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Chem. 908-913), 0.2 g of sodium acetate and 0.42 g of 2-dimethylaminoethoxyamine dichlorohydrate, in 70 ml of 96% ethanol was heated at 50C for two hours.
The organic solvent was removed by evaporation under reduced pressure and the residue was extracted with CH2Cl2 and water. The organic phase was separated, washed with water, dehydrated on anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude residue was dissolved in methanol (100 ml) and hydrolyzed in an acid environment as described in Ex. 4. After purification on a silica gel column using CH2Cl2/MeOH (90/10 v/v) as eluant; 0.15 g of the compound (I-i) as a white foam and 0.18 g of compound (I-l) as a yellowish foam were obtained.
(I-i) 1H-NMR(300MHz,CDCl3,ppm from TMS):1.05(3H,s); 1.28(3H,s);
2.27(3H,s); 2.35-3.10(6H,m); 4.08(2H,t); 4.14(1H,m);
4.25-4.95(2H,m); 5.91(1H,m); 7.36(1H,dd).
(I-l) 1H-NMR(300MHz,CDCl3,ppm from TMS):1.05(3H,s); 1.28(3H,s);
2.31(3H,s); 2.35-3.07(6H,m); 4.14(1H,m); 4.16(2H,t);
4.68-4.90(2H,m); 5.91 (lH~m); 6.57( lH,dd).
313-hydroxy-14-oxo-14.15-seco-513-card-20(22~ enolide-15-tE) -(~uanidin~
imino) (I-m) To a solution of 0.5 g of 3l3-acethoxy-14,15-dioxo-14,15-seco-5-l3-card-20(22)-enolide (IV) (Cohnen E., Wedemeier K., Sinnwell V. (1982).
Cardenolide, I. D-Ringspaltung von Cardenoliden. Liebigs Ann. Chem. 908-913) in 25 ml of a mixture (1: 1 v/v) of dioxane and water, 0.19 g of aminoguanidine bicarbonate dissolved in 10 ml of the same solvent mixture were added. The reaction mixture was heated at the reflux temperature for one hour and the organic solvent was removed by evaporation under reduced pressure. The aqueous suspension thus obtained was extracted with a (9:1 v/v) mixture of CHCl3/MeOH; the organic phase was separated, washed with a saturated solution of NaCl, dehydrated on anhydrous Na2SO4 and the solvent was removed by evaporation under reduced pressure. The residue thus obtained was treated with diluted acid as described in Ex, 4 and purified by silica gel chromatography using CHCl3/MeOH/NH4OH (80/20/2 v/v/v) as eluant. 0.15 g of the title compound were obtained as a white solid.
lH-NM~(300MHz,DMSO-D6,ppm from TMS): 0.99(3H,s); 1.19(3H,s);
2.01(3H,s); 2.30-2.70(3H,m); 3.18(1H,dd); 4.81(2H,m); 4.91(1H,m);
5.40-5.91(4H,bb); 6.02(1H,s); 7.23(1H,dd).
Claims (3)
1. Seco-D steroids of general formula (I) (I) wherein:
R is 3-furyl or 2,5-dihydro-5-oxo-3-furyl;
when R is 3-furyl the symbol represents a single bond;
R1 is methyl or hydroxymethyl;
R2 and R3 are OH and H respectively, or taken together form a keto group:
with the proviso that when R2 and R3 taken together form a keto group, R1 is methyl:
when R is 2,5-dihydro-5-oxo-3-furyl the symbol represents either a single or a double bond;
R1 is methyl, cyano or CH=N R4;
R2 and R3 have the above-specified meaning;
with the proviso that when R1 is CH=N R4, R2 and R3 taken together form a keto group;
with the proviso that when the symbol represents a double bond, R1 is methyl, and R2, R3 taken together form a keto group;
the symbol represents either the Z or the E isomer;
R4 is NHC(=NH)NR5R6 or OR7;
wherein R5, R6, equal or different, are H or C1-C4 alkyl; or R5, R6 taken together can possibly form, with the heteroatom they are linked to, a five- or six-membered monoheterocyclic ring;
R7 is H, CH3, C2-C6 alkyl, unsubstituted or substituted by NR8R9;
wherein R8 and R9, equal or different, are H or C1-C4 alkyl;
and the pharmaceutically acceptable salts thereof.
R is 3-furyl or 2,5-dihydro-5-oxo-3-furyl;
when R is 3-furyl the symbol represents a single bond;
R1 is methyl or hydroxymethyl;
R2 and R3 are OH and H respectively, or taken together form a keto group:
with the proviso that when R2 and R3 taken together form a keto group, R1 is methyl:
when R is 2,5-dihydro-5-oxo-3-furyl the symbol represents either a single or a double bond;
R1 is methyl, cyano or CH=N R4;
R2 and R3 have the above-specified meaning;
with the proviso that when R1 is CH=N R4, R2 and R3 taken together form a keto group;
with the proviso that when the symbol represents a double bond, R1 is methyl, and R2, R3 taken together form a keto group;
the symbol represents either the Z or the E isomer;
R4 is NHC(=NH)NR5R6 or OR7;
wherein R5, R6, equal or different, are H or C1-C4 alkyl; or R5, R6 taken together can possibly form, with the heteroatom they are linked to, a five- or six-membered monoheterocyclic ring;
R7 is H, CH3, C2-C6 alkyl, unsubstituted or substituted by NR8R9;
wherein R8 and R9, equal or different, are H or C1-C4 alkyl;
and the pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, which is selected from:
17.beta.-(3-furyl)- 14,15-seco-5.beta.-androstan-3.beta., 14.beta.-diol 17.beta.-(3-furyl)- 14,15-seco-5.beta.-androstan-31.beta., 14.beta.,15-triol
17.beta.-(3-furyl)- 14,15-seco-5.beta.-androstan-3.beta., 14.beta.-diol 17.beta.-(3-furyl)- 14,15-seco-5.beta.-androstan-31.beta., 14.beta.,15-triol
3.beta.-hydroxy- 17.beta.-(3-furyl)- 14,15-seco-5.beta.-androstan-14-one 3.beta.-hydroxy- 14-oxo- 14,15-seco-5.beta.-card-20(22)-enolide 3.beta..14.beta.-dihydroxy- 14,15-seco-5.beta.-card-20(22) -enolide 3.beta.-hydroxy- 14-oxo- 14,15-seco-5.beta.-card-8,20(22)-dienolide 3.beta.-hydroxy-14-oxo-14,15-seco-5.beta.-card-20(22)-enolide-15-nitrile 3.beta.,14.beta.-dihydroxy- 14,15-seco-5.beta.-card-20(22)-enolide- 15-nitrile 3.beta.-hydroxy- 14-oxo- 14,15-seco-5.beta.-card-20(22)enolide- 15-(2-dimethyl-aminoethoxy- (E)-iminoethyl) 3.beta.-hydroxy-14-oxo-14,15-seco-5.beta.-card-20(22)-enolide-15-(2-dimeth aminoethoxy- (Z)-iminoethyl) 3.beta.-hydroxy- 14-oxo- 14,15-seco-5.beta.-card-20(22)-enolide- 15-(E)-(guanidinimino).
3. A pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
3. A pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM95A000303 | 1995-05-11 | ||
| IT95RM000303A IT1282286B1 (en) | 1995-05-11 | 1995-05-11 | SECO-D STEROIDS ON THE CARDIOVASCULAR SYSTEM, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2174715A1 true CA2174715A1 (en) | 1996-11-12 |
Family
ID=11403363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002174715A Abandoned CA2174715A1 (en) | 1995-05-11 | 1996-04-22 | Seco-d steroids active on the cardiovascular system and pharmaceutical compositions containing same |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5731345A (en) |
| EP (1) | EP0742214B1 (en) |
| JP (1) | JPH09291086A (en) |
| AT (1) | ATE181324T1 (en) |
| CA (1) | CA2174715A1 (en) |
| DE (1) | DE69602886T2 (en) |
| DK (1) | DK0742214T3 (en) |
| ES (1) | ES2133918T3 (en) |
| GR (1) | GR3031118T3 (en) |
| IT (1) | IT1282286B1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19633376A1 (en) * | 1996-08-19 | 1998-02-26 | Sigma Tau Ind Farmaceuti | New Seco-D steroids that act on the cardiovascular system, processes for their preparation and pharmaceutical compositions containing them |
| WO1999061055A1 (en) | 1998-05-22 | 1999-12-02 | The Board Of Trustees Of The Leland Stanford Junior University | Bifunctional molecules and therapies based thereon |
| DE60234057D1 (en) | 2001-07-25 | 2009-11-26 | Raptor Pharmaceutical Inc | COMPOSITIONS AND METHODS FOR MODULATING TRANSPORT BY THE BLOOD-BRAIN BARRIER |
| US20040064050A1 (en) * | 2002-09-20 | 2004-04-01 | Jun Liu | System and method for screening tissue |
| DK1889198T3 (en) | 2005-04-28 | 2015-02-09 | Proteus Digital Health Inc | Pharma-informatics system |
| US9062126B2 (en) | 2005-09-16 | 2015-06-23 | Raptor Pharmaceuticals Inc. | Compositions comprising receptor-associated protein (RAP) variants specific for CR-containing proteins and uses thereof |
| ES2380491T3 (en) * | 2005-11-25 | 2012-05-14 | Rostaquo S.P.A. | Additional crystalline forms of Rostafuroxin |
| ES2728225T3 (en) | 2009-02-20 | 2019-10-23 | 2 Bbb Medicines B V | Glutathione based drug delivery system |
| EP2427178B1 (en) | 2009-05-06 | 2023-01-04 | Laboratory Skin Care, Inc. | Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4221538C1 (en) * | 1992-07-01 | 1994-03-31 | Sigma Tau Ind Farmaceuti | 14-deoxy-14alpha-cardenolide-3beta-thio derivatives |
| DE4221636C1 (en) * | 1992-07-01 | 1994-03-31 | Sigma Tau Ind Farmaceuti | Cyclopentane perhydrophenanthrene-17beta- (3-furyl) -3 derivatives |
| DE4227605C2 (en) * | 1992-08-20 | 1995-02-16 | Sigma Tau Ind Farmaceuti | 17-Hydroxyiminomethyl-14beta-hydroxy-5β-androstane derivatives, processes for their preparation and pharmaceutical compositions containing them |
-
1995
- 1995-05-11 IT IT95RM000303A patent/IT1282286B1/en active IP Right Grant
-
1996
- 1996-04-11 EP EP96830206A patent/EP0742214B1/en not_active Expired - Lifetime
- 1996-04-11 ES ES96830206T patent/ES2133918T3/en not_active Expired - Lifetime
- 1996-04-11 AT AT96830206T patent/ATE181324T1/en not_active IP Right Cessation
- 1996-04-11 DE DE69602886T patent/DE69602886T2/en not_active Expired - Fee Related
- 1996-04-11 DK DK96830206T patent/DK0742214T3/en active
- 1996-04-15 US US08/632,124 patent/US5731345A/en not_active Expired - Fee Related
- 1996-04-22 CA CA002174715A patent/CA2174715A1/en not_active Abandoned
- 1996-04-26 JP JP8106864A patent/JPH09291086A/en active Pending
-
1999
- 1999-08-31 GR GR990402200T patent/GR3031118T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK0742214T3 (en) | 1999-12-13 |
| IT1282286B1 (en) | 1998-03-16 |
| DE69602886D1 (en) | 1999-07-22 |
| ITRM950303A1 (en) | 1996-11-11 |
| DE69602886T2 (en) | 1999-11-04 |
| ITRM950303A0 (en) | 1995-05-11 |
| ATE181324T1 (en) | 1999-07-15 |
| US5731345A (en) | 1998-03-24 |
| EP0742214A1 (en) | 1996-11-13 |
| EP0742214B1 (en) | 1999-06-16 |
| GR3031118T3 (en) | 1999-12-31 |
| ES2133918T3 (en) | 1999-09-16 |
| JPH09291086A (en) | 1997-11-11 |
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Legal Events
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| FZDE | Discontinued |